Rheumatoid arthritis is a lifelong, crippling, multisystem disease whose principal manifestation is joint inflammation. The prevalence of definite rheumatoid arthritis in the United States is approximately 1 percent (2,400,000 individuals). This estimated prevalence increases to 3 percent (7,200,000 individuals) when a more liberal definition of disease as specified by the American Rheumatism Association ("probable" and "possible" rheumatoid arthritis) is applied.
In the majority of individuals the disease is characterized by a fluctuating and variable course with lifelong periods of exacerbation and regression, but with ever worsening joint deformity and systemic disability. Approximately 10 percent of patients develop only a short-lived inflammatory process which remits spontaneously without permanent residua, while at the opposite end of the spectrum another 10 percent experience a relentlessly progressive disease leading rapidly to marked deformity and disability. The principal manifestation of rheumatoid arthritis is joint inflammation and deformity, usually accompanied by constitutional symptoms such as weakness, easy fatigability, anorexia or weight loss. Approximately 10-20 percent of individuals with definite rheumatoid arthritis experience significant extra-articular manifestation including vasculitis, skeletal muscle weakness and atrophy, polyneuropathy, pleuropulmonary disease, pericarditis or hematologic abnormalities.
Chemotherapeutic agents available for the treatment of rheumatoid arthritis are characterized by low efficacy and high toxicity. These agents fall into categories including steroids, nonsteroidal anti-inflammatory agents (NSAID's) and disease modifying anti-rheumatoid drugs (DMARD's). The NSAID's which include salicylates, as well as ibuprofen, fenoprofen, naproxen, piroxicam, tolmetin, indomethacin, sulindac, meclofenamate and others are primariy cycloxygenase inhibitors, inhibiting production of prostaglandins, prostacycline and thromboxanes. Thus, they all produce nonspecific analgesic, anti-inflammatory and antipyretic effects and are prescribed for the control of a variety of inflammatory states. Although they are perceived to be quite potent, in fact none have been demonstrated to be more effective than aspirin in the treatment of rheumatoid arthritis. NSAID's are generally prescribed as first line therapy for this condition and are administered episodically for control of acute exacerbation of disease. Patients commonly develop tachyphylaxis or therapeutic tolerance to these agents over time and it is common practice for individuals to be switched frequently from one to another agent in the group. It is unclear whether such decreased efficacy is a function of disease progression or physiologic tolerance. Despite their status as first line treatment for rheumatoid arthritis, the NSAID's are associated with a wide spectrum of toxic side effects, especially at the doses needed to control rheumatoid arthritis. All are associated with gastrointestinal irritation (and bleeding), azotemia, platelet dysfunction, liver function abnormalities, bone marrow depression and exacerbation of allergic conditions such as rhinitis or asthma. Although the incidence of each of these effects varies somewhat with the specific agent, elderly patients receiving diuretics, common in populations with rheumatoid arthritis, may be at higher than average risk for such phenomena.
The classification of drugs as DMARD's is somewhat of a misomer as none of these agents have been clearly shown to modify the progression of rheumatoid arthritis, although some rheumatologists believe that D-penicillamine or gold may delay the progression of radiologic abnormalities. In fact the Food and Drug Administration (FDA) appear to prefer the designation SAARD's (slow acting anti-rheumatic drugs) to more accurately identify the most unifying feature of these agents--the fact that clinical efficacy does not appear for weeks or months. Drugs in the category include D-penicillamine, gold salts (both parenteral and oral forms), hydroxychloroquine, azathioprine, methotrexae and cyclophosphamide, although the latter three agents are often classified as cytotoxic agents rather than DMARD's. Due to their considerable toxicity, these drugs are usually employed as second line therapy after patients become less responsive to NSAID's, but are usually given in conjunction with an NSAID. Generally these drugs are reserved for patients only with the most severe forms of rheumatoid arthritis and are rarely used early in the course of the disease. Over the course of their disease, patients are frequently switched from one agent to another due to intolerable toxicity or progressive lack of efficacy. Unlike the former group of compounds, agents in this category may produce improvement in such serologic markers of disease activity as titers of rheumatoid factor or sedimentation rate. However, formidable toxicity is associated with each and "black box" warnings are incorporated into the FDA approved labelling for drugs in this category. Gold salts are associated with a high incidence of rash, bone marrow toxicity (occasionally life threatening), proteinuria and severe diarrhea whereas hydroxychloroquine is associated with retinopathy, blood dyscrasias and a high incidence of dermatologic abnormalities including depigmentation and alopecia. Approximately 30% of patients receiving D-penicillamine develop significant proteinuria. Thrombocytopenia, rash or taste disturbances are also common. Azathioprine and cyclophosphamide are both associated with severe gastrointestinal and hematologic abnormalities as well as with an increased risk or neoplasia.
In view of this lack of effective, reasonably nontoxic chemotherapy for the treatment of rheumatoid arthritis, many new agents are in various phases of clinical development, including a variety of NSAID's and NSAID-prodrugs; gamma interferon, eicosapentaenoic acid, cyclosporin, interleuken-1 inhibitors, PAF antagonists and other immunomodulating agents are exemplary.
Dixon et al., "Biochemical and Clinical Changes Occurring During the Treatment of Rheumatoid Arthritis with Novel Antirheumatoid Drugs", International Journal of Clinical Pharmacology in Research, V(1):25-33 (1985) report that while it would be useful to discover more compounds with antirheumatoid activity, there are no adequate animal models of rheumatoid arthritis for the assessment of such compounds. A human screening system is reported by Dixon et al. and the testing of captopril in that system is also reported. Antirheumatoid activity is reported for captopril based on the results of that screening. Captopril is an angiotensin converting enzyme inhibitor having the chemical name 1-[(2S)-3- mercapto-2-methylpropionyl]-L-proline.
Jaffe, "Adverse Effects Profile of Sulfhydryl Compounds in Man", American Journal of Medicine, 80:471 (March, 1986) describes the use of sufhydryl containing compounds in the treatment of rheumatoid arthritis. The compounds described are penicillamine, 5-thiopyridoxine, pyrithioxine, .alpha.-mercaptopropionylglycine and captopril. In discussing these compounds, Jaffe states "Although these compounds show considerable variation in their chemical structure . . . , the sulfhydryl group is the fundamental requirement for antirheumatic activity in all of them." In discussing the need for more compounds in this class, Jaffe also states "Unfortunately, there is currently no means of predicting either efficacy or toxicity, short of an individual clinical trial".
(cis)-1-[D-3-(Benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylthio)-L-proline (and its pharmaceutically acceptable salts) is an angiotensin converting enzyme inhibitor; see, for example, U.S. Pat. No. 4,316,906; issued February 23, 1982, which describes the compound and its salts. The approved nonproprietary name of the compound is zofenopril. Zofenopril is a prodrug of (cis)-1-(D-3-mercapto-2-methyl-1-oxopropyl)-4-(phenylthio)-L-proline.